Role of ependyma in forebrain homeostasis

室管膜在前脑稳态中的作用

• 批准号: 9169677
• 负责人: Hooman Troy Ghashghaei
• 金额: $ 32.52万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169677
• 关键词: Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Attention; Biochemical; Biological Assay; Biological Markers; Blood Circulation; Blood Vessels; Boxing; Brain; Cells; Cerebrospinal Fluid; Communicable Diseases; Defect; Dementia; Disease; Elderly; Ependyma; Ependymal Cell; Epithelium; Etiology; Filtration; Functional disorder; Genetic; Homeostasis; Human; Immune; Impaired cognition; In Vitro; Infection; Inflammation; Inflammatory; Lead; Life; Lymph; Lymphatic System; Lymphatic vessel; MARCKS gene; Maintenance; Maps; Measures; Mediating; Memory; Meninges; Metabolic; Modeling; Molecular; Mucins; Mus; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Physiological; Plant Roots; Population; Probability; Production; Prosencephalon; Protein Isoforms; Proteomics; Publications; Publishing; Regulation; Research Proposals; Role; Signal Transduction; Staging; Stress; System; Testing; Tissue imaging; Tissues; Toxin; Waste Products; aging brain; base; brain parenchyma; cognitive capacity; cognitive performance; conditioned fear; glymphatic system; healthy aging; inflammatory marker; interstitial; monolayer; mouse model; nervous system disorder; new therapeutic target; normal aging; novel; public health relevance; response; spatial memory; therapeutic target; toxicant; trafficking; ventricular system

Project Description The high probability of breakdown in the functioning of the central nervous system (CNS) during late stages of aging, as in Alzheimer’s disease and various dementias is a major concern for the elderly. Triggers that initiate age-associated diseases and neurological conditions are for the most part unknown. A key to these associations could be the population of ependymal cells in the brain. Ependymal cells form a monolayer that functions as a barrier between the cerebrospinal fluid (CSF) and the overlying cellular compartments of the brain. As such, they regulate CSF production, circulation, and filtering, and thus ependymal cells are a key component of the newly described ‘glymphtic-lymphatic’ system. This system is purported to control CSF- vascular interactions in the brain parenchyma and thus contribute to the overall clearance of the brain of toxicants and metabolic byproducts and allow entry of immune cells into the brain. The ependymal layer appears damaged in the aged brain, yet whether the damage is caused by malfunctioning signals in the overlying CNS tissue, or if ependymal damage causes defects in neurons and glia in the CNS remain unknown. We have developed several genetic mouse models which suggest the ependymal layer may be the root of many problems in the brain interstitium related to various neurodegenerative diseases and during normal aging in the CNS. We will use these models to study this novel concept. Studies in our mouse models have revealed a previously unknown expression and clearance of mucins by ependymal cells in the CNS. Since mucins function to protect against inflammation and infectious diseases in other tissues, our results have led to the central hypothesis that mucin secretion by ependymal cells is required for maintenance and functional integrity of homeostasis in the forebrain during aging, and that disruption of mucin secretion can lead to aberrant function and disease in the CNS. Our project uses a variety of genetic mice, together with cellular, molecular, and biochemical approaches to test our hypothesis. Potential for Broader Impact: Our approaches to understand how aging affects the brain through its monolayer of ependymal cells have wide implications. Disruption of filtration and protective functions of ependymal cells may be the root of a range of pathological conditions that emerge during late stages of aging. Therefore, undertaking the basic cellular mechanisms that control aging of the brain is critical to understanding not only how healthy aging may be controlled by ependymal cells, but also how abnormalities in ependymal aging may lead to devastating diseases such as Alzheimer’s. Moreover, the mechanisms we study can be harnessed to develop novel aging therapeutics by targeting ependymal functions selectively.

项目描述 中枢神经系统（CNS）在晚期的后期崩溃的可能性很高 老化，就像阿尔茨海默氏病和各种痴呆症一样，这是一个主要问题。触发启动的人 与年龄相关的疾病和神经系统疾病在很大程度上是未知的。这些关键 关联可能是大脑中的室系室细胞的种群。室室室形成一个单层，该单层 充当脑脊液（CSF）与上覆的细胞室之间的障碍 脑。因此，它们调节CSF的产生，循环和滤波，因此是室心膜细胞是关键 新描述的“ Glymphtic-lymphatic”系统的组成部分。据称该系统可以控制CSF- 大脑实质中的血管相互作用，因此有助于大脑的整体清除 有毒物质和代谢副产品，并允许将免疫细胞进入大脑。室系层 在老化的大脑中似乎受损 上覆的CNS组织，或者如果室系损伤导致CNS神经元和神经胶质的缺陷，则保留 未知。我们已经开发了几种遗传小鼠模型，这表明室室层可能是 与各种神经退行性疾病有关的大脑间质中许多问题的根源 中枢神经系统中的正常衰老。我们将使用这些模型研究这个新颖的概念。在我们的鼠标模型中的研究 已经揭示了CNS中室心脑室细胞的先前未知表达和粘蛋白的清除。 由于粘蛋白在其他时候可防止炎症和传染病来防止炎症和感染性疾病，因此我们的结果具有 导致了一个中心假设，即维持和 衰老期间，稳态的功能完整性和粘蛋白分泌的破坏可以带领 在中枢神经系统中的异常功能和疾病。我们的项目使用各种遗传小鼠，以及细胞， 分子和生化方法检验我们的假设。 产生更广泛影响的潜力：我们了解衰老如何通过其影响大脑影响大脑的方法 室系室细胞的单层具有广泛的影响。过滤和保护功能的破坏 室室室细胞可能是衰老后期出现的一系列病理状况的根源。 因此，采取控制大脑衰老的基本细胞机制对于理解至关重要 不仅可以通过室心室细胞控制健康衰老，还可以如何控制室心室的异常 衰老可能导致毁灭性疾病，例如阿尔茨海默氏症。而且，我们研究的机制可以是 通过选择性地靶向室室功能，可以利用开发新的衰老治疗。